With this mentored award, Dr. Lisette Acevedo will develop both scientific and career skills in the laboratory of Dr. David Cheresh necessary to successfully pursue her goal of becoming a Professor of Pathology or Pharmacology at a school of medicine. This proposal describes a five year training program for the development of an academic career under the primary mentorship of Dr. Cheresh. Career and research project development will also include structured activities such as presenting annually at the Moores Cancer Center Research Rounds. As an Assistant Project Scientist in the University of California, San Diego Department of Pathology and Moores Cancer Center, Dr. Acevedo will have the opportunity to consult with a diverse group of highly accomplished faculty which can provide further assistance in achieving her career goals. She will also receive additional career mentorship from Dr. Francisco Villarreal, who will provide more structured guidance in strengthening the non-research skills needed for a successful independent academic career. The goal of the proposed research project is to examine the role of semaphorin 3A (Sema3A) signaling in tumor cell extravasation and metastasis. We find that Sema3A expression is higher in more metastatic cell lines. During her tenure in the Cheresh lab, Dr. Acevedo successfully published a manuscript identifying Sema3A as a novel permeability factor, thereby opening this new area of research and making her uniquely qualified to carry out the proposed work. Now Dr. Acevedo will expand upon her scientific skills to include the pathological consequences of Sema3A expression by tumor cells on vascular permeability and metastasis. Specifically she will utilize in vitro and in vivo models to exam how Sema3A signaling through its receptor Nrp1 may disrupt VE-cadherin-regulated the endothelial junctions and allow tumor cell invasion into the underlying tissue. As part of her scientific training, she will also oversee laboratory technicians which will assist with experiments. This research project will combine molecular/cell biological approaches with in vivo assays of vascular permeability, extravasation, and metastasis. With this career development award Dr. Acevedo will not only enhance her scientific skills, but also gain career skills that will assist her in becoming a successful professor at a research intensive medical school. PUBLIC HEALTH RELEVANCE: Tumor cells can disseminate and colonize distal sites, in part, by regulating vascular permeability. This allows them to transmigrate through disrupted endothelial junctions and invade the underlying tissue. The candidate recently identified Sema3A as a novel permeability factor. With this mentored career development award, the candidate plans to study the role in tumor cell extravasation and metastasis. Understanding how mediators of vascular permeability can affect tumor extravasation and metastasis is required to design novel approaches to control metastatic disease.